TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.

Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.

“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”

In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.

The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.

Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).

On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.

She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”

For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”

Dr. Lauw reported having no financial disclosures.

dbrunk@frontlinemedcom.com

TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.

Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.

“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”

In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.

The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.

Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).

On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.

She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”

For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”

Dr. Lauw reported having no financial disclosures.

dbrunk@frontlinemedcom.com

TORONTO – The use of statins showed no benefit in reducing the risk of recurrent venous thromboembolism in patients enrolled in phase III trials comparing direct oral anticoagulants with vitamin K antagonists, a large meta-analysis demonstrated.

Recurrence after an unprovoked VTE is 10%-15% in the first 6-12 months, and recurrence risk in the first 6 months is reduced by 80%-90% with anticoagulants, Dr. Mandy N. Lauw said at the International Society on Thrombosis and Haemostasis congress.

“However, the use of anticoagulants has the risk of bleeding, and therefore the long-term risk-benefit ratio is unclear,” said Dr. Lauw of the department of vascular medicine at Academic Medical Center, Amsterdam. “Therefore it’s interesting to look at modalities outside the coagulation cascade to treat patients for longer term and to prevent recurrent thrombosis. One of these modalities has been the use of statins, which are known to reduce arterial vascular events by lowering cholesterol levels. However, recent studies have also indicated that they may have an effect on VTE events.”

In an effort to evaluate the effects of statins on recurrent VTE, Dr. Lauw and her associates conducted a meta-analysis of statins in three randomized, phase III trials comparing non–vitamin K oral anticoagulant (NOAC) with vitamin K antagonist (VKA) therapy in patients with acute symptomatic VTE.

The trials included 5,153 patients enrolled in RE-COVER I and II (an analysis of dabigatran vs. standard therapy for acute VTE), 8,281 enrolled in the EINSTEIN clinical trials for DVT and pulmonary embolism (an analysis of rivaroxaban vs. standard therapy for symptomatic VTE), and 8,292 enrolled in a trial conducted by the Hokusai-DVT investigators (an analysis of edoxaban vs. standard therapy for symptomatic VTE). The researchers examined the effect of statin use on recurrent VTE or VTE-related death, recurrent DVT or PE, and major bleeding. To do this they conducted a pooled meta-analysis and an analysis per study, adjusted for age, gender, diabetes mellitus, creatinine clearance of less than 50 mL/min, hypertension, prior VTE, and use of aspirin.

Dr. Lauw reported results from 21,587 patients included in the analysis. Among all three studies, 2,754 patients (12.8%) used statins and 18,833 (87.2%) did not. In an unadjusted pooled analysis, the use of statins at baseline did not have an influence on the risk of recurrent VTE or VTE-related death, with an odds ratio of 0.91. There was also no effect of statins on the risk of recurrent PE or DVT (ORs of 0.84 and 1.05, respectively), while major bleeding seemed to be increased with the use of statins (OR, 1.65). A subanalysis in patients getting NOAC or VKA separately showed a non–statistically significant benefit of statins with NOACs, compared with VKAs on the risk of recurrent VTE or VTE-related death (ORs of 0.60 vs. OR 1.24, respectively). The results were similar for NOACs, compared with VKA, on the risk of recurrent DVT (ORs of 0.47 vs. OR 1.67) and the risk of recurrent PE (ORs of 0.73 vs. 1.02).

On adjusted analysis, the risk of recurrent VTE or VTE-related death between all three studies was similar and nonsignificant (hazard ratio of 0.99 in RE-COVER I and II, HR of 0.78 in the EINSTEIN clinical trials for DVT & PE, and HR of 0.99 in the trial conducted by the Hokusai-DVT Investigators). There also were no significant differences between the study groups in recurrent PE, recurrent DVT, or major bleeding. “So statins have no beneficial effect, but also no harmful effect,” Dr. Lauw said.

She acknowledged certain limitations of the study, including the fact that it was an on-treatment analysis, “so it could be that we had inadequate follow-up duration,” she said. “Also, we don’t have any assessment of statin effects without anticoagulation in these patients. Perhaps it would be interesting to use the extension trials to explore these results as well.”

For now, “there is no evidence that statins reduce the recurrence of VTE,” she concluded. “The only way to explore this is to do a randomized controlled trial properly designed and powered to estimate this effect prospectively.”

Dr. Lauw reported having no financial disclosures.

dbrunk@frontlinemedcom.com

Preet Chaudhary, MD, PhD,

reviewing an image

Photo from the University

of Southern California

Immunomodulatory drugs (IMiDs) and BRD4 inhibitors hold promise for treating primary effusion lymphoma (PEL), according to preclinical research.

The IMiDs lenalidomide and pomalidomide had antiproliferative effects in PEL cell lines, and lenalidomide exhibited synergistic cytotoxicity with the BRD4 inhibitors JQ-1, IBET151, and PFI-1.

In mouse models of PEL, treatment with lenalidomide and JQ-1 significantly prolonged survival.

Preet Chaudhary, MD, PhD, of the University of Southern California, Los Angeles, and his colleagues reported these results in Oncogene.

The researchers first tested lenalidomide and pomalidomide in 9 PEL cell lines. Both drugs exhibited antiproliferative effects, at clinically achievable doses, in 6 of the cell lines (BC-3, BCBL-1, JSC-1, VG-1, UMPEL-1, and UMPEL-3).

The IMiDs displayed activity in the remaining 3 cells lines (BC-1, BCP-1, and APK-1) as well, but only at high doses (ranging from 2.6 μM to 10 μM for lenalidomide and from 226 nM to 744 nM for pomalidomide).

Looking into the mechanism of IMiDs in PEL, the researchers found these drugs induce G1 cell-cycle arrest without inducing Kaposi’s sarcoma-associated herpes virus lytic cycle reactivation.

Further investigation revealed that interferon α, β, and γ are cytotoxic to PEL, but they are not essential for the antiproliferative effects of IMiDs. On the other hand, cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1 are essential.

The researchers also found that knocking down MYC enhanced IMiD activity. This led them to BRD4 inhibitors, which are known to target MYC transcription.

The team tested lenalidomide in combination with JQ-1, IBET151, and PFI-1. The IMiD was “highly synergistic” with all 3 BRD4 inhibitors in BC-3 and BCBL-1 cell lines.

In both cell lines, treatment with lenalidomide and JQ-1 significantly decreased the expression of MYC and IRF4 at protein and mRNA levels. The treatment also resulted in G1 cell cycle arrest, cleavage of poly (ADP-ribose) polymerase, and apoptosis.

So the researchers tested this combination in a mouse model of PEL (NOD-SCID mice injected with BC-3 cells). And they observed a significant improvement in median survival for mice that received combination treatment, compared to lenalidomide or JQ-1 alone—51 days, 35 days, and 42 days, respectively (P≤0.01).

Preet Chaudhary, MD, PhD,

reviewing an image

Photo from the University

of Southern California

Immunomodulatory drugs (IMiDs) and BRD4 inhibitors hold promise for treating primary effusion lymphoma (PEL), according to preclinical research.

The IMiDs lenalidomide and pomalidomide had antiproliferative effects in PEL cell lines, and lenalidomide exhibited synergistic cytotoxicity with the BRD4 inhibitors JQ-1, IBET151, and PFI-1.

In mouse models of PEL, treatment with lenalidomide and JQ-1 significantly prolonged survival.

Preet Chaudhary, MD, PhD, of the University of Southern California, Los Angeles, and his colleagues reported these results in Oncogene.

The researchers first tested lenalidomide and pomalidomide in 9 PEL cell lines. Both drugs exhibited antiproliferative effects, at clinically achievable doses, in 6 of the cell lines (BC-3, BCBL-1, JSC-1, VG-1, UMPEL-1, and UMPEL-3).

The IMiDs displayed activity in the remaining 3 cells lines (BC-1, BCP-1, and APK-1) as well, but only at high doses (ranging from 2.6 μM to 10 μM for lenalidomide and from 226 nM to 744 nM for pomalidomide).

Looking into the mechanism of IMiDs in PEL, the researchers found these drugs induce G1 cell-cycle arrest without inducing Kaposi’s sarcoma-associated herpes virus lytic cycle reactivation.

Further investigation revealed that interferon α, β, and γ are cytotoxic to PEL, but they are not essential for the antiproliferative effects of IMiDs. On the other hand, cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1 are essential.

The researchers also found that knocking down MYC enhanced IMiD activity. This led them to BRD4 inhibitors, which are known to target MYC transcription.

The team tested lenalidomide in combination with JQ-1, IBET151, and PFI-1. The IMiD was “highly synergistic” with all 3 BRD4 inhibitors in BC-3 and BCBL-1 cell lines.

In both cell lines, treatment with lenalidomide and JQ-1 significantly decreased the expression of MYC and IRF4 at protein and mRNA levels. The treatment also resulted in G1 cell cycle arrest, cleavage of poly (ADP-ribose) polymerase, and apoptosis.

So the researchers tested this combination in a mouse model of PEL (NOD-SCID mice injected with BC-3 cells). And they observed a significant improvement in median survival for mice that received combination treatment, compared to lenalidomide or JQ-1 alone—51 days, 35 days, and 42 days, respectively (P≤0.01).

Preet Chaudhary, MD, PhD,

reviewing an image

Photo from the University

of Southern California

Immunomodulatory drugs (IMiDs) and BRD4 inhibitors hold promise for treating primary effusion lymphoma (PEL), according to preclinical research.

The IMiDs lenalidomide and pomalidomide had antiproliferative effects in PEL cell lines, and lenalidomide exhibited synergistic cytotoxicity with the BRD4 inhibitors JQ-1, IBET151, and PFI-1.

In mouse models of PEL, treatment with lenalidomide and JQ-1 significantly prolonged survival.

Preet Chaudhary, MD, PhD, of the University of Southern California, Los Angeles, and his colleagues reported these results in Oncogene.

The researchers first tested lenalidomide and pomalidomide in 9 PEL cell lines. Both drugs exhibited antiproliferative effects, at clinically achievable doses, in 6 of the cell lines (BC-3, BCBL-1, JSC-1, VG-1, UMPEL-1, and UMPEL-3).

The IMiDs displayed activity in the remaining 3 cells lines (BC-1, BCP-1, and APK-1) as well, but only at high doses (ranging from 2.6 μM to 10 μM for lenalidomide and from 226 nM to 744 nM for pomalidomide).

Looking into the mechanism of IMiDs in PEL, the researchers found these drugs induce G1 cell-cycle arrest without inducing Kaposi’s sarcoma-associated herpes virus lytic cycle reactivation.

Further investigation revealed that interferon α, β, and γ are cytotoxic to PEL, but they are not essential for the antiproliferative effects of IMiDs. On the other hand, cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1 are essential.

The researchers also found that knocking down MYC enhanced IMiD activity. This led them to BRD4 inhibitors, which are known to target MYC transcription.

The team tested lenalidomide in combination with JQ-1, IBET151, and PFI-1. The IMiD was “highly synergistic” with all 3 BRD4 inhibitors in BC-3 and BCBL-1 cell lines.

In both cell lines, treatment with lenalidomide and JQ-1 significantly decreased the expression of MYC and IRF4 at protein and mRNA levels. The treatment also resulted in G1 cell cycle arrest, cleavage of poly (ADP-ribose) polymerase, and apoptosis.

So the researchers tested this combination in a mouse model of PEL (NOD-SCID mice injected with BC-3 cells). And they observed a significant improvement in median survival for mice that received combination treatment, compared to lenalidomide or JQ-1 alone—51 days, 35 days, and 42 days, respectively (P≤0.01).

Angiogenesis

Image by Louis Heiser

and Robert Ackland

Scientists say they have developed a model that provides new insight into chaotic angiogenesis, a hallmark of cancer.

The model shows how proteins involved in angiogenesis communicate with each other and how tumors take charge of the protein signaling chain that controls blood vessel growth.

The work, published in PNAS, suggests that Jagged ligands play a major role in the chaotic vessel growth observed around tumors.

In normal growth, an endothelial cell sprouts from an existing blood vessel as a tip. Others that follow the tip cell become the stalk cells that ultimately form vessel walls. The Notch signaling pathway directs the endothelial cell’s decision to become a tip or stalk.

Notch receptors bind with Delta ligand or Jagged ligand molecules produced by cells. How they interact determines the cell’s fate.

When Notch and Delta bind, they prompt a few cells to be tips and adjacent ones to be stalks. The Notch-Delta pathway has been studied extensively and is the target of many angiogenesis inhibitors now in use, according to the scientists.

“We wondered exactly what Notch-Jagged signaling does that is not done in Notch-Delta signaling,” said study author Marcelo Boareto, PhD, of the Swiss Federal Institute of Technology in Zurich.

“We find that when the cells communicate mostly via Jagged, we see a new kind of cell that is not exactly tip and not exactly stalk, but somewhere in between. This compromised cell is the major difference between normal and tumor angiogenesis and suggests that if Notch-Jagged signaling can be somehow suppressed without affecting Notch-Delta, we can probably disrupt tumor angiogenesis.”

The scientists found the tip/stalk hybrid cells do form new blood vessels, but these vessels rarely mature.

“High levels of Jagged in the environment can trigger the formation of blood vessels that are useful to the tumor: fast-developing, leaky, and spread chaotically all over the tumor mass,” Dr Boareto said.

“Tumors don’t have to wait for the vessels to develop,” added study author José Onuchic, PhD, of Rice University in Houston, Texas. “They take advantage of the leakiness of the structure.”

The scientists’ model also takes into account the effect of vascular endothelial growth factor, which triggers angiogenesis and is overexpressed by tumor cells.

“It is very interesting how the tumor hijacks this important mechanism, which is needed for the development of a functional vessel, and amplifies it to generate pathological angiogenesis that leads to uncontrolled growth,” Dr Onuchic said.

Angiogenesis

Image by Louis Heiser

and Robert Ackland

Scientists say they have developed a model that provides new insight into chaotic angiogenesis, a hallmark of cancer.

The model shows how proteins involved in angiogenesis communicate with each other and how tumors take charge of the protein signaling chain that controls blood vessel growth.

The work, published in PNAS, suggests that Jagged ligands play a major role in the chaotic vessel growth observed around tumors.

In normal growth, an endothelial cell sprouts from an existing blood vessel as a tip. Others that follow the tip cell become the stalk cells that ultimately form vessel walls. The Notch signaling pathway directs the endothelial cell’s decision to become a tip or stalk.

Notch receptors bind with Delta ligand or Jagged ligand molecules produced by cells. How they interact determines the cell’s fate.

When Notch and Delta bind, they prompt a few cells to be tips and adjacent ones to be stalks. The Notch-Delta pathway has been studied extensively and is the target of many angiogenesis inhibitors now in use, according to the scientists.

“We wondered exactly what Notch-Jagged signaling does that is not done in Notch-Delta signaling,” said study author Marcelo Boareto, PhD, of the Swiss Federal Institute of Technology in Zurich.

“We find that when the cells communicate mostly via Jagged, we see a new kind of cell that is not exactly tip and not exactly stalk, but somewhere in between. This compromised cell is the major difference between normal and tumor angiogenesis and suggests that if Notch-Jagged signaling can be somehow suppressed without affecting Notch-Delta, we can probably disrupt tumor angiogenesis.”

The scientists found the tip/stalk hybrid cells do form new blood vessels, but these vessels rarely mature.

“High levels of Jagged in the environment can trigger the formation of blood vessels that are useful to the tumor: fast-developing, leaky, and spread chaotically all over the tumor mass,” Dr Boareto said.

“Tumors don’t have to wait for the vessels to develop,” added study author José Onuchic, PhD, of Rice University in Houston, Texas. “They take advantage of the leakiness of the structure.”

The scientists’ model also takes into account the effect of vascular endothelial growth factor, which triggers angiogenesis and is overexpressed by tumor cells.

“It is very interesting how the tumor hijacks this important mechanism, which is needed for the development of a functional vessel, and amplifies it to generate pathological angiogenesis that leads to uncontrolled growth,” Dr Onuchic said.

Angiogenesis

Image by Louis Heiser

and Robert Ackland

Scientists say they have developed a model that provides new insight into chaotic angiogenesis, a hallmark of cancer.

The model shows how proteins involved in angiogenesis communicate with each other and how tumors take charge of the protein signaling chain that controls blood vessel growth.

The work, published in PNAS, suggests that Jagged ligands play a major role in the chaotic vessel growth observed around tumors.

In normal growth, an endothelial cell sprouts from an existing blood vessel as a tip. Others that follow the tip cell become the stalk cells that ultimately form vessel walls. The Notch signaling pathway directs the endothelial cell’s decision to become a tip or stalk.

Notch receptors bind with Delta ligand or Jagged ligand molecules produced by cells. How they interact determines the cell’s fate.

When Notch and Delta bind, they prompt a few cells to be tips and adjacent ones to be stalks. The Notch-Delta pathway has been studied extensively and is the target of many angiogenesis inhibitors now in use, according to the scientists.

“We wondered exactly what Notch-Jagged signaling does that is not done in Notch-Delta signaling,” said study author Marcelo Boareto, PhD, of the Swiss Federal Institute of Technology in Zurich.

“We find that when the cells communicate mostly via Jagged, we see a new kind of cell that is not exactly tip and not exactly stalk, but somewhere in between. This compromised cell is the major difference between normal and tumor angiogenesis and suggests that if Notch-Jagged signaling can be somehow suppressed without affecting Notch-Delta, we can probably disrupt tumor angiogenesis.”

The scientists found the tip/stalk hybrid cells do form new blood vessels, but these vessels rarely mature.

“High levels of Jagged in the environment can trigger the formation of blood vessels that are useful to the tumor: fast-developing, leaky, and spread chaotically all over the tumor mass,” Dr Boareto said.

“Tumors don’t have to wait for the vessels to develop,” added study author José Onuchic, PhD, of Rice University in Houston, Texas. “They take advantage of the leakiness of the structure.”

The scientists’ model also takes into account the effect of vascular endothelial growth factor, which triggers angiogenesis and is overexpressed by tumor cells.

“It is very interesting how the tumor hijacks this important mechanism, which is needed for the development of a functional vessel, and amplifies it to generate pathological angiogenesis that leads to uncontrolled growth,” Dr Onuchic said.

Doctor and patient in hospital

Photo courtesy of the CDC

Hospital readmissions for sepsis are under-recognized, and additional measures are needed to prevent these readmissions, researchers say.

The group conducted a study of California hospitals that showed sepsis accounts for roughly the same percentage of readmissions as heart attacks and congestive heart failure.

However, sepsis readmissions cost the healthcare system more than heart attack and congestive heart failure readmissions combined.

The research was published in Critical Care Medicine.

“Our study shows how common sepsis readmissions are and [elucidates] some of the factors that are associated with higher risk of readmission after these severe infections,” said study author Dong Chang, MD, of Harbor-UCLA Medical Center in Los Angeles, California.

“In addition, we show that sepsis readmissions have a significant impact on healthcare expenditures relative to other high-risk conditions that are receiving active attention and interventions. Based on these results, we believe that sepsis readmissions are under-recognized and should be among the conditions that are targeted for intervention by policymakers.”

The researchers analyzed data on sepsis admissions for adults 18 years of age and older at all California hospitals from 2009 through 2011. The team also analyzed data for congestive heart failure and heart attack admissions during the same period.

There were 240,198 admissions for sepsis, 193,153 for congestive heart failure, and 105,684 for heart attacks. The all-cause, 30-day readmission rate was 20.4% for sepsis, 23.6% for congestive heart failure, and 17.7% for heart attacks.

Patients with sepsis were readmitted because of respiratory failure; pneumonia; urinary tract infections; renal infections; renal failure; intestinal infections; complications with devices, implants, or grafts; and other causes.

Sepsis readmission rates were higher among young adults than older adults, among men than women, among black and Native American patients than other racial groups, and among lower-income patients than those with higher incomes. In addition, patients with other concurrent health problems were more likely to be readmitted than those with sepsis alone.

The estimated annual cost of sepsis-related readmissions in California during the study period was $500 million, compared with $229 million for congestive heart failure and $142 million for heart attacks.

“These findings suggest that efforts to reduce hospital readmissions need to include sepsis prominently, at least on par with heart failure and myocardial infarction,” said study author Martin Shapiro, MD, PhD, of the David Geffen School of Medicine at UCLA.

Next, the researchers plan to examine why patients are readmitted after sepsis and the percentage of those readmissions that are due to processes that can be improved upon, such as discharge practices, follow-up care, and teaching patients how to take their medications.

Doctor and patient in hospital

Photo courtesy of the CDC

Hospital readmissions for sepsis are under-recognized, and additional measures are needed to prevent these readmissions, researchers say.

The group conducted a study of California hospitals that showed sepsis accounts for roughly the same percentage of readmissions as heart attacks and congestive heart failure.

However, sepsis readmissions cost the healthcare system more than heart attack and congestive heart failure readmissions combined.

The research was published in Critical Care Medicine.

“Our study shows how common sepsis readmissions are and [elucidates] some of the factors that are associated with higher risk of readmission after these severe infections,” said study author Dong Chang, MD, of Harbor-UCLA Medical Center in Los Angeles, California.

“In addition, we show that sepsis readmissions have a significant impact on healthcare expenditures relative to other high-risk conditions that are receiving active attention and interventions. Based on these results, we believe that sepsis readmissions are under-recognized and should be among the conditions that are targeted for intervention by policymakers.”

The researchers analyzed data on sepsis admissions for adults 18 years of age and older at all California hospitals from 2009 through 2011. The team also analyzed data for congestive heart failure and heart attack admissions during the same period.

There were 240,198 admissions for sepsis, 193,153 for congestive heart failure, and 105,684 for heart attacks. The all-cause, 30-day readmission rate was 20.4% for sepsis, 23.6% for congestive heart failure, and 17.7% for heart attacks.

Patients with sepsis were readmitted because of respiratory failure; pneumonia; urinary tract infections; renal infections; renal failure; intestinal infections; complications with devices, implants, or grafts; and other causes.

Sepsis readmission rates were higher among young adults than older adults, among men than women, among black and Native American patients than other racial groups, and among lower-income patients than those with higher incomes. In addition, patients with other concurrent health problems were more likely to be readmitted than those with sepsis alone.

The estimated annual cost of sepsis-related readmissions in California during the study period was $500 million, compared with $229 million for congestive heart failure and $142 million for heart attacks.

“These findings suggest that efforts to reduce hospital readmissions need to include sepsis prominently, at least on par with heart failure and myocardial infarction,” said study author Martin Shapiro, MD, PhD, of the David Geffen School of Medicine at UCLA.

Next, the researchers plan to examine why patients are readmitted after sepsis and the percentage of those readmissions that are due to processes that can be improved upon, such as discharge practices, follow-up care, and teaching patients how to take their medications.

Doctor and patient in hospital

Photo courtesy of the CDC

Hospital readmissions for sepsis are under-recognized, and additional measures are needed to prevent these readmissions, researchers say.

The group conducted a study of California hospitals that showed sepsis accounts for roughly the same percentage of readmissions as heart attacks and congestive heart failure.

However, sepsis readmissions cost the healthcare system more than heart attack and congestive heart failure readmissions combined.

The research was published in Critical Care Medicine.

“Our study shows how common sepsis readmissions are and [elucidates] some of the factors that are associated with higher risk of readmission after these severe infections,” said study author Dong Chang, MD, of Harbor-UCLA Medical Center in Los Angeles, California.

“In addition, we show that sepsis readmissions have a significant impact on healthcare expenditures relative to other high-risk conditions that are receiving active attention and interventions. Based on these results, we believe that sepsis readmissions are under-recognized and should be among the conditions that are targeted for intervention by policymakers.”

The researchers analyzed data on sepsis admissions for adults 18 years of age and older at all California hospitals from 2009 through 2011. The team also analyzed data for congestive heart failure and heart attack admissions during the same period.

There were 240,198 admissions for sepsis, 193,153 for congestive heart failure, and 105,684 for heart attacks. The all-cause, 30-day readmission rate was 20.4% for sepsis, 23.6% for congestive heart failure, and 17.7% for heart attacks.

Patients with sepsis were readmitted because of respiratory failure; pneumonia; urinary tract infections; renal infections; renal failure; intestinal infections; complications with devices, implants, or grafts; and other causes.

Sepsis readmission rates were higher among young adults than older adults, among men than women, among black and Native American patients than other racial groups, and among lower-income patients than those with higher incomes. In addition, patients with other concurrent health problems were more likely to be readmitted than those with sepsis alone.

The estimated annual cost of sepsis-related readmissions in California during the study period was $500 million, compared with $229 million for congestive heart failure and $142 million for heart attacks.

“These findings suggest that efforts to reduce hospital readmissions need to include sepsis prominently, at least on par with heart failure and myocardial infarction,” said study author Martin Shapiro, MD, PhD, of the David Geffen School of Medicine at UCLA.

Next, the researchers plan to examine why patients are readmitted after sepsis and the percentage of those readmissions that are due to processes that can be improved upon, such as discharge practices, follow-up care, and teaching patients how to take their medications.

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

Bleomycin can be eliminated after two cycles of the ABVD chemotherapeutic regimen based on a negative interim PET scan finding in patients with Hodgkin lymphoma, according to the 3-year findings of the RATHL study.

Being able to omit bleomycin after a negative interim PET scan was associated with a lower rate of pulmonary toxicity, but no loss in efficacy. For patients with positive interim PET scans, a more aggressive therapy was associated with good outcomes, suggesting that response-adapted therapy can yield good results, Dr. Peter Johnson said at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In the large international RATHL study (Response-Adapted Therapy in Hodgkin Lymphoma study) 1,137 adults with newly diagnosed disease (41% stage II, 31% stage III, 28% stage IV) underwent PET-CT scans at baseline and after completing two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The patients’ PET images were centrally reviewed using a 5-point scale as either negative (1-3) or positive (4-5),

The majority of patients (84%) had negative scans after two cycles of the ABVD regimen and were randomized to receive four additional cycles either with or without bleomycin (ABVD or AVD). Consolidation radiotherapy was not advised for patients whose interim PET scans were negative, regardless of baseline bulk or residual masses, Dr. Johnson, of the Cancer Research UK Centre at University of Southampton, England, reported.

Patients with positive interim PET scans received escalated therapy with a BEACOPP (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, prednisolone) regimen. They received either eBEACOPP and BEASCOPP-14.

At the 3-year follow-up, progression-free survival in the PET-negative group was 85% for both the ABVD- and AVD-treated patients. Similarly, overall survival was 97% for both groups.

Factors that predicted treatment failure after a negative interim PET scan were initial tumor stage and international prognostic score, but not bulk, B symptoms, or score of the interim PET scan.

ABVD was associated with more pulmonary toxicity than was AVD.

Of 174 patients who had a positive interim PET scan and received escalated therapy, 74% had a subsequent negative PET scan after treatment. Their 3-year, progression-free survival rate was 68%, and their overall survival was 86% with no difference in outcome between two variations of BEACOPP (eBEACOPP and BEASCOPP-14).

Of the 53 deaths in the study, 19 were caused by Hodgkin lymphoma. The overall 3-year progression-free survival is 83%, and overall survival is 95%.

The results of the RATHL study have important implications for therapy of Hodgkin lymphoma, Dr. Johnson stated. First, interim PET scans are highly predictive for response to ABVD, providing valuable prognostic information to support decisions related to escalation of therapy. Secondly, after two cycles of ABVD, “it is safe to omit bleomycin from subsequent cycles, without consolidation radiotherapy,” he reported.

Omitting bleomycin has the potential to reduce pulmonary toxicity from chemotherapy, especially dyspnea, thromboembolism, and neutropenic fever, Dr. Johnson added. In the RATHL study, rates of pulmonary toxicity were significantly higher in the group receiving bleomycin.

Bleomycin can be eliminated after two cycles of the ABVD chemotherapeutic regimen based on a negative interim PET scan finding in patients with Hodgkin lymphoma, according to the 3-year findings of the RATHL study.

Being able to omit bleomycin after a negative interim PET scan was associated with a lower rate of pulmonary toxicity, but no loss in efficacy. For patients with positive interim PET scans, a more aggressive therapy was associated with good outcomes, suggesting that response-adapted therapy can yield good results, Dr. Peter Johnson said at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In the large international RATHL study (Response-Adapted Therapy in Hodgkin Lymphoma study) 1,137 adults with newly diagnosed disease (41% stage II, 31% stage III, 28% stage IV) underwent PET-CT scans at baseline and after completing two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The patients’ PET images were centrally reviewed using a 5-point scale as either negative (1-3) or positive (4-5),

The majority of patients (84%) had negative scans after two cycles of the ABVD regimen and were randomized to receive four additional cycles either with or without bleomycin (ABVD or AVD). Consolidation radiotherapy was not advised for patients whose interim PET scans were negative, regardless of baseline bulk or residual masses, Dr. Johnson, of the Cancer Research UK Centre at University of Southampton, England, reported.

Patients with positive interim PET scans received escalated therapy with a BEACOPP (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, prednisolone) regimen. They received either eBEACOPP and BEASCOPP-14.

At the 3-year follow-up, progression-free survival in the PET-negative group was 85% for both the ABVD- and AVD-treated patients. Similarly, overall survival was 97% for both groups.

Factors that predicted treatment failure after a negative interim PET scan were initial tumor stage and international prognostic score, but not bulk, B symptoms, or score of the interim PET scan.

ABVD was associated with more pulmonary toxicity than was AVD.

Of 174 patients who had a positive interim PET scan and received escalated therapy, 74% had a subsequent negative PET scan after treatment. Their 3-year, progression-free survival rate was 68%, and their overall survival was 86% with no difference in outcome between two variations of BEACOPP (eBEACOPP and BEASCOPP-14).

Of the 53 deaths in the study, 19 were caused by Hodgkin lymphoma. The overall 3-year progression-free survival is 83%, and overall survival is 95%.

The results of the RATHL study have important implications for therapy of Hodgkin lymphoma, Dr. Johnson stated. First, interim PET scans are highly predictive for response to ABVD, providing valuable prognostic information to support decisions related to escalation of therapy. Secondly, after two cycles of ABVD, “it is safe to omit bleomycin from subsequent cycles, without consolidation radiotherapy,” he reported.

Omitting bleomycin has the potential to reduce pulmonary toxicity from chemotherapy, especially dyspnea, thromboembolism, and neutropenic fever, Dr. Johnson added. In the RATHL study, rates of pulmonary toxicity were significantly higher in the group receiving bleomycin.

Bleomycin can be eliminated after two cycles of the ABVD chemotherapeutic regimen based on a negative interim PET scan finding in patients with Hodgkin lymphoma, according to the 3-year findings of the RATHL study.

Being able to omit bleomycin after a negative interim PET scan was associated with a lower rate of pulmonary toxicity, but no loss in efficacy. For patients with positive interim PET scans, a more aggressive therapy was associated with good outcomes, suggesting that response-adapted therapy can yield good results, Dr. Peter Johnson said at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In the large international RATHL study (Response-Adapted Therapy in Hodgkin Lymphoma study) 1,137 adults with newly diagnosed disease (41% stage II, 31% stage III, 28% stage IV) underwent PET-CT scans at baseline and after completing two cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The patients’ PET images were centrally reviewed using a 5-point scale as either negative (1-3) or positive (4-5),

The majority of patients (84%) had negative scans after two cycles of the ABVD regimen and were randomized to receive four additional cycles either with or without bleomycin (ABVD or AVD). Consolidation radiotherapy was not advised for patients whose interim PET scans were negative, regardless of baseline bulk or residual masses, Dr. Johnson, of the Cancer Research UK Centre at University of Southampton, England, reported.

Patients with positive interim PET scans received escalated therapy with a BEACOPP (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, prednisolone) regimen. They received either eBEACOPP and BEASCOPP-14.

At the 3-year follow-up, progression-free survival in the PET-negative group was 85% for both the ABVD- and AVD-treated patients. Similarly, overall survival was 97% for both groups.

Factors that predicted treatment failure after a negative interim PET scan were initial tumor stage and international prognostic score, but not bulk, B symptoms, or score of the interim PET scan.

ABVD was associated with more pulmonary toxicity than was AVD.

Of 174 patients who had a positive interim PET scan and received escalated therapy, 74% had a subsequent negative PET scan after treatment. Their 3-year, progression-free survival rate was 68%, and their overall survival was 86% with no difference in outcome between two variations of BEACOPP (eBEACOPP and BEASCOPP-14).

Of the 53 deaths in the study, 19 were caused by Hodgkin lymphoma. The overall 3-year progression-free survival is 83%, and overall survival is 95%.

The results of the RATHL study have important implications for therapy of Hodgkin lymphoma, Dr. Johnson stated. First, interim PET scans are highly predictive for response to ABVD, providing valuable prognostic information to support decisions related to escalation of therapy. Secondly, after two cycles of ABVD, “it is safe to omit bleomycin from subsequent cycles, without consolidation radiotherapy,” he reported.

Omitting bleomycin has the potential to reduce pulmonary toxicity from chemotherapy, especially dyspnea, thromboembolism, and neutropenic fever, Dr. Johnson added. In the RATHL study, rates of pulmonary toxicity were significantly higher in the group receiving bleomycin.

Value-based healthcare has to start from the beginning of training to become foundational to medical practice. In this interview, Dr. Wade Iams, Dr. Christopher Moriates, and Dr. Vineet Arora, talk about getting value-based principles embedded in medical school curricula.

Value-based healthcare has to start from the beginning of training to become foundational to medical practice. In this interview, Dr. Wade Iams, Dr. Christopher Moriates, and Dr. Vineet Arora, talk about getting value-based principles embedded in medical school curricula.

Value-based healthcare has to start from the beginning of training to become foundational to medical practice. In this interview, Dr. Wade Iams, Dr. Christopher Moriates, and Dr. Vineet Arora, talk about getting value-based principles embedded in medical school curricula.

Adult survivors of cancer who were diagnosed between the ages of 11 and 21 years self-reported higher rates of impairment in emotional and neurocognitive outcomes compared with their sibling counterparts, according to researchers.

Compared with siblings, survivors reported greater anxiety (odds ratio [OR], 2.0; 95% CI, 1.17-3.43), somatization (2.36; 1.55-3.60), and depression (1.55; 1.04-2.30). Higher rates of neurocognitive problems included task efficiency (1.72; 1.21-2.43), emotional regulation (1.74; 1.26-2.40), and memory (1.44; 1.09-1.89). Survivors were significantly less likely to be employed (P < .001).

Previous reports have shown that survivors of childhood cancers have increased risk for impaired neurocognitive functioning, but this is the first study to examine outcomes in survivors who were diagnosed during adolescence and early young adulthood.

“Cancer treatment during this time has the potential to interfere with adolescents’ separation from caregivers, autonomy with regard to planning social and academic schedules, participation in social activities, and maintaining privacy, particularly of their bodies,” wrote Dr. Pinki Prasad, assistant professor of pediatrics at Louisiana State University, New Orleans.

Survivors who were diagnosed with CNS tumors or leukemia during adolescence reported rates of emotional distress and neurocognitive dysfunction similar to rates of those diagnosed during early childhood, whereas diagnoses of lymphoma/sarcoma during adolescence resulted in lower risk of impairment compared with early childhood diagnoses. This may be due to the fact that the leukemia/CNS tumor group was more likely to receive cranial radiation therapy, a predictor of neurocognitive late effects, Dr. Prasad and colleagues wrote (J. Clin. Oncol. 2015 July 6 [doi:10.1200/JCO.2014.57.7528]).

Among those diagnosed with lymphomas or sarcomas during adolescence, treatment with corticosteroids was associated with greater risk of self-reported difficulties with somatization, anxiety, task efficiency, and memory.

The Childhood Cancer Survivor Study (CCSS) is a multicenter, retrospective cohort study that comprised 2,589 survivors who were diagnosed from 1970 through 1986 when they were between the ages 11 and 21 years, and 360 sibling counterparts. Participants completed the Brief Symptom Inventory–18, which measures symptoms of emotional distress, and the CCSS Neurocognitive Questionnaire.

The authors noted that the results indicate “high rates of self-reported impairment in neurocognitive function and psychological distress that are associated with limitation in development of adult social milestones,” and that further follow-up with survivors of adolescent and early young adult cancers may be necessary.

Adult survivors of cancer who were diagnosed between the ages of 11 and 21 years self-reported higher rates of impairment in emotional and neurocognitive outcomes compared with their sibling counterparts, according to researchers.

Compared with siblings, survivors reported greater anxiety (odds ratio [OR], 2.0; 95% CI, 1.17-3.43), somatization (2.36; 1.55-3.60), and depression (1.55; 1.04-2.30). Higher rates of neurocognitive problems included task efficiency (1.72; 1.21-2.43), emotional regulation (1.74; 1.26-2.40), and memory (1.44; 1.09-1.89). Survivors were significantly less likely to be employed (P < .001).

Previous reports have shown that survivors of childhood cancers have increased risk for impaired neurocognitive functioning, but this is the first study to examine outcomes in survivors who were diagnosed during adolescence and early young adulthood.

“Cancer treatment during this time has the potential to interfere with adolescents’ separation from caregivers, autonomy with regard to planning social and academic schedules, participation in social activities, and maintaining privacy, particularly of their bodies,” wrote Dr. Pinki Prasad, assistant professor of pediatrics at Louisiana State University, New Orleans.

Survivors who were diagnosed with CNS tumors or leukemia during adolescence reported rates of emotional distress and neurocognitive dysfunction similar to rates of those diagnosed during early childhood, whereas diagnoses of lymphoma/sarcoma during adolescence resulted in lower risk of impairment compared with early childhood diagnoses. This may be due to the fact that the leukemia/CNS tumor group was more likely to receive cranial radiation therapy, a predictor of neurocognitive late effects, Dr. Prasad and colleagues wrote (J. Clin. Oncol. 2015 July 6 [doi:10.1200/JCO.2014.57.7528]).

Among those diagnosed with lymphomas or sarcomas during adolescence, treatment with corticosteroids was associated with greater risk of self-reported difficulties with somatization, anxiety, task efficiency, and memory.

The Childhood Cancer Survivor Study (CCSS) is a multicenter, retrospective cohort study that comprised 2,589 survivors who were diagnosed from 1970 through 1986 when they were between the ages 11 and 21 years, and 360 sibling counterparts. Participants completed the Brief Symptom Inventory–18, which measures symptoms of emotional distress, and the CCSS Neurocognitive Questionnaire.

The authors noted that the results indicate “high rates of self-reported impairment in neurocognitive function and psychological distress that are associated with limitation in development of adult social milestones,” and that further follow-up with survivors of adolescent and early young adult cancers may be necessary.

Adult survivors of cancer who were diagnosed between the ages of 11 and 21 years self-reported higher rates of impairment in emotional and neurocognitive outcomes compared with their sibling counterparts, according to researchers.

Compared with siblings, survivors reported greater anxiety (odds ratio [OR], 2.0; 95% CI, 1.17-3.43), somatization (2.36; 1.55-3.60), and depression (1.55; 1.04-2.30). Higher rates of neurocognitive problems included task efficiency (1.72; 1.21-2.43), emotional regulation (1.74; 1.26-2.40), and memory (1.44; 1.09-1.89). Survivors were significantly less likely to be employed (P < .001).

Previous reports have shown that survivors of childhood cancers have increased risk for impaired neurocognitive functioning, but this is the first study to examine outcomes in survivors who were diagnosed during adolescence and early young adulthood.

“Cancer treatment during this time has the potential to interfere with adolescents’ separation from caregivers, autonomy with regard to planning social and academic schedules, participation in social activities, and maintaining privacy, particularly of their bodies,” wrote Dr. Pinki Prasad, assistant professor of pediatrics at Louisiana State University, New Orleans.

Survivors who were diagnosed with CNS tumors or leukemia during adolescence reported rates of emotional distress and neurocognitive dysfunction similar to rates of those diagnosed during early childhood, whereas diagnoses of lymphoma/sarcoma during adolescence resulted in lower risk of impairment compared with early childhood diagnoses. This may be due to the fact that the leukemia/CNS tumor group was more likely to receive cranial radiation therapy, a predictor of neurocognitive late effects, Dr. Prasad and colleagues wrote (J. Clin. Oncol. 2015 July 6 [doi:10.1200/JCO.2014.57.7528]).

Among those diagnosed with lymphomas or sarcomas during adolescence, treatment with corticosteroids was associated with greater risk of self-reported difficulties with somatization, anxiety, task efficiency, and memory.

The Childhood Cancer Survivor Study (CCSS) is a multicenter, retrospective cohort study that comprised 2,589 survivors who were diagnosed from 1970 through 1986 when they were between the ages 11 and 21 years, and 360 sibling counterparts. Participants completed the Brief Symptom Inventory–18, which measures symptoms of emotional distress, and the CCSS Neurocognitive Questionnaire.

The authors noted that the results indicate “high rates of self-reported impairment in neurocognitive function and psychological distress that are associated with limitation in development of adult social milestones,” and that further follow-up with survivors of adolescent and early young adult cancers may be necessary.

Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&amp;E,original magnification ×100).

Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&amp;E,original magnification ×100).

Hair pigmentation is a complex phenomenon that involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu.¹ Repigmentation of gray hair has been associated with herpes zoster infection,² use of systemic corticosteroids,³ thyroid hormone therapy,⁴ or treatment with interferon and ribavirin.⁵ We report a case of repigmentation of gray hairs in lesions of annular elastolytic giant cell granuloma (AEGCG) on the scalp of a 67-year-old man.

Case Report

A 67-year-old man presented to the dermatology department for evaluation of pruritic lesions on the face and scalp of 1 year’s duration. The patient reported that hairs in the involved areas of the scalp had turned from gray to a dark color since the appearance of the lesions. The patient had a history of hypertension and type 2 diabetes mellitus. His current medications included irbesartan, atorvastatin, metformin, acetylsalicylic acid, omeprazole, and repaglinide.

Physical examination revealed plaques on the scalp and cheeks that were 2 to 10 mm in diameter. Some of the plaques had an atrophic center and a desquamative peripheral border. The patient had androgenetic alopecia. The remaining hair was dark in the areas affected by the inflammatory plaques while it remained white-gray in the uninvolved areas (Figure 1).

Figure 1. Repigmentation of gray hair in the areas affected by plaques on the scalp.

A biopsy of one of the lesions was performed. Histopathology revealed a granulomatous dermatitis involving mostly the upper and mid dermis (Figure 2). Granulomas were epithelioid with many giant cells, some of which contained many nuclei. A ringed array of nuclei was noted in some histiocytes. Elastic fibers were absent in the central zone of the granulomas, a finding that was better evidenced on orcein staining (Figure 3). On the contrary, the peripheral zone of the granulomas showed an increased amount of thick elastotic material. Elastophagocytosis was observed, but no asteroid bodies, Schaumann bodies, or mucin deposits were noted. Histochemistry for microorganisms with Ziehl-Neelsen and periodic acid–Schiff staining was negative. Other findings included a mild infiltrate of melanophages in the papillary dermis as well as a mild superficial dermal inflammatory infiltrate that was rich in plasma cells. Immunostaining for Treponema pallidum was negative. The lymphocytic infiltrate was CD4⁺predominant. A prominent dermal elastosis also was noted. Hair follicles within the plaques were small in size, penetrating just the dermis. Immunostaining for HMB-45, melan-A, and S-100 demonstrated preserved melanocytes in the hair bulbs (Figure 4). CD68 immunostaining made the infiltrate of macrophages stand out. Based on the results of the histopathologic evaluation, a diagnosis of AEGCG was made.

Figure 2. Biopsy showed granulomatous dermatitis in which many giant cells were seen. The latter contained several nuclei, sometimes in a ringed array (H&E, original magnification ×20).

Figure 3. Orcein stain demonstrated a decrease in elastic fibers in the center of the granulomas as well as an increase of elastic fibers in the periphery. Elastophagocytosis was easily observed (original magnification ×40).

Figure 4. Immunohistochemical staining for HMB-45 showed preservation of melanocytes in the hair bulbs (original magnification ×20).

Comment

Annular elastolytic giant cell granuloma is a controversial entity that was first described by O’Brien⁶ in 1975 as actinic granuloma. Hanke et al⁷ proposed the term annular elastolytic giant cell granuloma to encompass lesions previously called actinic granuloma, atypical necrobiosis lipoidica, and Miescher granuloma. Some researchers have claimed that AEGCG is an independent entity, therefore separate and distinguishable from granuloma annulare. Histopathologic clues to distinguish AEGCG from granuloma annulare have been noted in the literature.^7-9 Other investigators believe AEGCG is a type of granuloma annulare that appears on exposed skin.¹⁰ There are several variants of the classic clinical presentation of AEGCG, such as cases including presentation in unexposed areas of the skin,¹¹ a papular variant,¹² a rapidly regressive variant,¹³ a reticular variant,¹⁴ a variant of early childhood,¹⁵ a generalized variant,¹⁶ presentation in a necklace distribution,¹⁷ presentation as alopecia,¹⁸ a sarcoid variant,¹⁹ or presentation as reticulate erythema.²⁰ However, no variant has been associated with hair repigmentation.

Melanin units from the proximal hair bulb are responsible for pigmentation in adult hair follicles and are integrated by the hair matrix, melanocytes, keratinocytes, and fibroblasts.²¹ Hair bulb melanocytes are larger and more dendritic than epidermal melanocytes (Figure 5). The hair only pigments during the anagen phase; therefore, its pigmentation is cyclic, as opposed to epidermal pigmentation, which is ongoing. Hair pigmentation is the result of a complex interaction between the epithelium, the mesenchyme, and the neuroectoderm. This complex pigmentation results from the interaction between follicular melanocytes, keratinocytes, and the fibroblasts from the hair papilla.²² Hair pigmentation involves many hormones, neurotransmitters, cytokines, growth factors, eicosanoids, cyclic nucleotides, nutrients, and a physicochemical milieu^1,23-25 (Table), and it is regulated by autocrines, paracrines, or intracrines.²¹ Therefore, it is likely that many environmental factors may affect hair pigmentation, which may explain why repigmentation of the hair has been seen in the setting of herpes zoster infection,² use of systemic corticosteroids in the treatment of bullous pemphigoid,³ thyroid hormone therapy,⁴ treatment with interferon and ribavirin,⁵ porphyria cutanea tarda,²⁶ or lentigo maligna.²⁷ In our patient, AEGCG might have induced some changes in the dermal environment that were responsible for the repigmentation of the patient’s gray hair. It is speculated that solar radiation and other factors can transform the antigenicity of elastic fibers and induce an immune response in AEGCG.^12,15 The lymphocytic infiltrate in these lesions is predominantly CD4⁺, as seen in our patient, which is consistent with an autoimmune hypothesis.¹⁵ Nevertheless, it most likely is too simplistic to attribute the repigmentation to the influence of just these cells.

Figure 5. A hair bulb of a normal follicle showing the morphology of melanocytes, which are dendritic and large (H&amp;E,original magnification ×100).

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.

The medical profession has its jargon. So does the Internet world. Some of that jargon can be important to your success. “Backlinks” or “inbound links” are terms that should get your attention.

Why?

By developing them, you can attract more patients to your practice.

Backlinks are one piece of the Internet marketing puzzle that can help get your Web site on the first page of Google search results.

And just how important is it to be on page 1?

Well, consider that 91.5% of Web surfers do not go beyond the first page of results. That’s what an online advertising network called Chitika found when it examined tens of millions of online ad impressions in which the user was referred to the page via a Google search.¹

Just what are backlinks? They are links to your Web page from another site. In basic link terminology, a backlink is any link received by a Web page, directory, Web site, or top-level domain from another, similar site. In this article we discuss the importance of these links and ways to use them in your social media to attract new patients to your site and your practice.

Start with good site design
If you can get listed on the first page of Google search results for the keywords your patients are using, more traffic will come to your Web site. That won’t help if you have a poorly designed site that has no patient conversion strategies, techniques, and systems to transform Web site visitors to patients.

You see, everything has to work together in a coordinated, integrated manner if you want to increase the number of patients who are looking for your services online. We’ve covered many of the basics in earlier articles on Web site design and improvement (see the box below). If you have a nonoptimal site, consider starting with these articles.

Why backlinks are important
Google uses more than 200 algorithms to rank your Web site. Some are more important than others and have a greater influence on search engine positioning. Backlinks are one of those important influencers.

The number of backlinks you have is an indication of the popularity or importance of your Web site. Google considers a site more significant or relevant than others if it has a large number of quality backlinks from other directories, ezines, blogs, and social media Web sites. These backlinks must be relevant to your keywords. For example, because you are a medical professional, a link to your site from the American Cancer Society or the Mayo Clinic is considered more credible than a link from a local spa or health club.

A search engine such as Google considers the content of the sites it places at the top of the search results page. When links to your site come from other credible and popular sites, and those sites have content related to your site, these backlinks are considered more relevant to your site.

If backlinks come from sites with unrelated content, they are considered less relevant. You may even be penalized by Google for adding backlinks that have no content value.

For example, if a Web master has a site that focuses on urinary incontinence and receives a backlink from another site with information or articles about urinary incontinence, that backlink will be considered more relevant than a link from a site about mortgages that somehow also includes urinary incontinence on its page. Therefore, the higher the relevance of the site linking back to yours, the better the quality of that link.

Top 7 inbound links—and how to obtain them
1. Directories
Directories are indexes of online sites, typically organized by category. You want to ensure that each of your keywords is manually submitted to each directory so it is listed separately. This way you get maximum link value for each keyword.

Links back to your site from directories such as Yahoo Directory and DMOZ.org are valuable. DMOZ.org is edited by humans. Although it is free, it may take some time for your site to be added. A listing in Yahoo’s Directory costs $299 per year.

2. Press releases
If you are writing press releases, make sure they contain keywords that someone would use to find a business like yours. Also ensure that they include links back to your site.

Once the press release is written, submit it to all the news agencies. Then you must wait and see if any of them pick it up and publish it.

You may want to consider having a press release professionally written and distributed by a public relations firm to boost your chances of having the release picked up. PRWeb.com has an excellent reputation. Its distribution network includes the search engines Google, Yahoo, and Bing; media outlets such as USA Today, CNN, and the Wall Street Journal; Associated Press distribution through major newspapers; and health and medical digests such as the Mayo Clinic, WebMD, Women’s Health, and many more.

3. Article directories
By writing and distributing articles through high-traffic article directories, such as EzineArticles.com, Articles.org, and Hubpages.com, you can attract valuable inbound links from a high-traffic site. Craft an effective link at the close of your article to drive traffic back to your site. An example of what your link might say is, “To view a short video on Kegel exercises for pelvic organ prolapse, visit our Web site at www.neilbaum.com/videos.”

4. Social bookmarking
Like Web browser bookmarks, social bookmarking sites such as Digg.com, Reddit.com, and Del.icio.us.com store individual pages (bookmarks) online and allow users to tag (with keywords), organize, search, and manage these bookmarks as well as share them with others. If you bookmark your content on these sites, you get a link from the service. By producing content that your readers enjoy and bookmark to their friends, you gain a link that increases in search engine optimization (SEO) value.

5. Blog comments
To find blog posts on which to comment, you can use blog-specific search engines such as Google Blog Search. Make sure these are blogs read by your target market, not your colleagues. Brand yourself by always using the same name and remember to link back to your site. Always leave a comment that adds to the conversation.

6. Social media
Google also indexes your Twitter updates and social networking profiles. Add that to Web 2.0 hubsites like Scribd or HubPage and you’ve got a way to create many inbound links in a very short time. Scribd is a digital library featuring an ebook and audiobook subscription service that includes New York Times best sellers and classics. HubPages is a user-generated content, revenue-sharing Web site.

7. Video syndication
YouTube is one of the most visited sites online, and the number of sites that syndicate videos is growing every day. These sites often allow you to link to your site in your video’s description, on your profile page, or both.

The importance of being consistent—and honest
For best results, you need to build these links monthly with regularity, and over time, you will reap the benefits of improved rankings. While it is fairly easy to modify your Web pages to make them more SEO-friendly, it is harder to influence other Web sites and get them to link to yours. This is the reason search engines consider backlinks such an important factor.

Moreover, search engines’ criteria for quality backlinks have gotten tougher, thanks to unscrupulous Web masters trying to achieve these backlinks by deceptive techniques, such as hidden links or automatically generated pages whose sole purpose is to provide backlinks to Web sites. These pages are called link farms. Not only are they disregarded by search engines, but linking to one could get your site banned entirely. This strategy is often referred to as “black hat” linking and is to be avoided.

“White hat” methods to increase backlinks
Blog posting is one of the easiest, least expensive, and most effective ways to garner links from other sites. However, to reap this benefit, you must post blog entries consistently. We suggest posting at least once weekly. Your blog will gain more attention if you have something newsworthy to report. For example, if you attend a meeting where a revolutionary new development is reported, and you write about it before the media, you can be sure others will want to connect and link to your site.

Conduct a survey and share your results on your site. Others will want to link to your report.

Share any templates your office uses to be more efficient and productive. For example, Dr. Baum has a template, or checklist, for starting and ending every day in the office. It is shared on his Web site so that other sites can link to it and make use of it.

Show your funny bone. Humor often travels in a viral direction. If something funny happens in your practice, share it with others and they will frequently link to the source.

Join a forum. Forums are a great source of high-quality traffic and links. You can use a forum to reach out to a specific community.By placing valid, useful contributions, you gain legitimate authority for your site.

The bottom line
You want to attract as many visitors to your Web site as possible. Your own content and the frequency of your postings are mainstays of making your Web site relevant to existing and potential patients. Also useful are backlinks. The number and quality of your inbound links are major factors in SEO. Search engines place high value on trust and authority, and an inbound link from a very high-ranking and trusted Web site tells the search engine that someone trusted also trusts you. So start linking.